Remaining tumor deposits are often a fatal complication from oncologic surgery, causing significant risk of recurrence along with decreased quality of life and high health care costs. Removal of tumor improves outcome but is often limited by the surgeon's ability to delineate small tumor deposits, therefore a method to improve visualization of tumors during surgery would have great benefit for the outcome of cancer patients. Optical imaging relates naturally to surgical inspection and practice. While a multitude of optical imaging agents have been developed, almost none have made it into the clinic. The long and costly regulatory process of fluorochromes hampers clinical translation; fluorescence imaging suffers from tissue autofluorescence and non-linearity. On the other hand, nuclear imaging provides multiple established and safe clinical tracers. It has been used for intraoperative detection for decades. A method to utilize these clinical radiotracers in conjunction with optical imaging would close this gap and introduce a variety of targeted imaging agent for intraoperative optical imaging. Combining nuclear and optical imaging, Cerenkov luminescence imaging (CLI) poses an opportunity to harness the strength of both approaches by using existing radiotracers for intra- operative optical imaging. CLI is the weak light emission from radioactive decay. It combines the intra- operative feasibility of optical imaging with the high diagnostic performance of radiotracers. In this study, we will facilitate clinical CLI and evaluate it in two settings: a) percutaneous detection of malignant lymph nodes and b) image-guided surgery with intraoperative CLI of endometrial cancer, whose incidence and mortality is increasing. The project will employ an innovative ultra-sensitive fiberoptic imaging device currently under development by our industrial partner Lightpoint Medical. This device allows CLI under ambient lighting with continuous monitoring of the surgical field. The project represents a multidisciplinary partnership between surgeons, radiologists, and engineer-entrepreneurs to develop a unique approach to improve cancer surgery methodology and improve its outcome. This study can transform the way how we treat cancer. Our central hypothesis is that CLI allows clinical optical imaging of tumors with radiotracers. Based on our extensive previous results, we now move CLI to a new level by proposing these 3 specific aims: (1) preclinical evaluation of the device; (2) clinical validation on percutaneous CLI of hypermetabolic lymph nodes; and lastly (3) feasibility of intraoperative CLI to increase the number of detected lesions. We are evaluating improved tumor detection by CLI in endometrial cancer surgery. This research is significant as it makes clinical radiotracers available for optica imaging, constituting a paradigm shift by merging nuclear with optical imaging. This research is innovative as it expands the application of nuclear tracers into a completely new clinical imaging paradigm. It brings experts in gynecologic oncologic surgery and Cerenkov imaging together with a startup company with the joined aim of translating CLI into the clinical arena for image guided surgery.